1. Field of the Invention
The present invention relates to improvements in the synthesis of certain 3-methyl cephem derivatives, viz., cephalexin or cephradine, by the acylation of silyl esters of 7-ADCA. In particular, it relates to an improved recovery technique for obtaining such materials in good yields and purities.
2. Description of the Prior Art
Cephalexin and cephradine are antibacterial agents of the class of compounds commonly referred to as cephalosporins. Numerous disclosures of alternative methods for the production and purification of cephalexin and cephradine, their salts and hydrates, have appeared in the technical literature over the past twenty years.
In accordance with one commercially important synthesis, cephalexin or cephradine may be prepared by silylating 7-aminodesacetoxycephalosporanic acid (7-ADCA), reacting the resulting silyl ester with an appropriate acylating agent, cleaving the silyl protecting groups, and raising the pH of the reaction mixture to the isoelectric point to precipitate the desired product. Syntheses of this type are disclosed, for example, in British Patent No. 1,073,530; Japanese Patent Publication No. 41-3907 (1966); Weissenburger et al. U.S. Pat. Nos. 3,499,909 and 3,575,970; and Jackson U.S. Pat. Nos. 3,671,449 and 3,694,437. Similar procedures have also been proposed for the synthesis of the related 3-methyl cephem, cefadroxil; see, for example, Bouzard et al. U.S. Pat. No. 4,234,721 and Reissue Patent Re. 31730.
The acylation step in the cephalexin synthesis is conventionally carried out with an acylating agent comprising an N-protonated acyl halide of phenylglycine (or, in the case of cephradine, an N-protonated acyl halide of dihydrophenyl-glycine), e.g., alpha-phenyl-glycylchloride hydrochloride. During acylation with such materials, a strong protic acid, e.g., hydrogen chloride, forms as a by-product, impeding further reaction. It is thus necessary to carry out the acylation in the presence of an acid (HCl) acceptor, preferably a nitrogen base such as N,N'-dimethylaniline. Too strong an acid acceptor will strip the HX from the nitrogen of the acid halide and give by-products. Likewise, too weak an acid acceptor will not trap the HX formed.
Heretofore, the desired 3-methyl cephem products have been recovered by cleaving the silyl protective groups by hydrolysis or alcoholysis, and thereafter raising the pH of the resulting aqueous acidic solution to the isoelectric point to precipitate the cephalexin or cephradine. Unfortunately, the products thus recovered may be contaminated with the acid acceptor, e.g., the dimethylaniline, intimately combined with cephalexin or cephradine. To overcome this problem a variety of techniques have heretofore been proposed in an effort to avoid contamination by the organic acid acceptors, including very carefully controlled crystallizations, extensive washings, recrystallizations, etc.
It is among the objects of the present invention to provide an improved technique for recovering 3-methyl cephems synthesized by the acylation of silyl esters of 7-ADCA in the presence of an acid acceptor, by which technique the desired products may be recovered in good yields and purities, substantially free from contamination by the acid acceptor.
Other objects and advantages of the invention will appear from the following description of preferred embodiments thereof.